Structural complexity of the co-chaperone SGTA: a conserved C-terminal region is implicated in dimerization and substrate quality control.
Structural complexity of the co-chaperone SGTA: a conserved C-terminal region is implicated in dimerization and substrate quality control.
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DOI：
10.1186/s12915-018-0542-3
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发表时间：
2018-07-11
期刊：
影响因子：
5.4
通讯作者：
Isaacson RL
中科院分区：
文献类型：
--
作者：
Martínez-Lumbreras S;Krysztofinska EM;Thapaliya A;Spilotros A;Matak-Vinkovic D;Salvadori E;Roboti P;Nyathi Y;Muench JH;Roessler MM;Svergun DI;High S;Isaacson RL
蛋白质质量控制机制对细胞健康至关重要，并涉及将蛋白质递送到特定的细胞区室进行再循环或降解。特别是，杂散疏水性蛋白质被捕获在含水的胞质溶胶中的辅分子伴侣，小谷氨酰胺丰富，tetratricopeptide repeat-containing蛋白α（SGTA），这有利于正确靶向的尾部锚定的膜蛋白，以及分选膜和分泌蛋白，错误定位到胞质溶胶和内质网相关的降解。全长SGTA具有不寻常的细长二聚体结构，到目前为止，这种结构一直无法进行详细的结构分析。SGTA的C-末端区域在结合广泛的疏水底物中起关键作用，然而与充分表征的N-末端和TPR结构域相反，缺乏关于C-末端结构域的结构信息。在这项研究中，我们提出了新的见解SGTA的不同结构域的构象和组织，并表明，C-末端结构域具有一个保守的区域在体内底物加工所必需的。我们发现，C-末端结构域区域的特征在于α-螺旋倾向和独立于N-末端结构域的内在二聚化能力。基于使用细胞生物学、NMR、SAXS、天然MS和EPR揭示的SGTA不同区域的性质，我们观察到其C-末端结构域可以在全长蛋白中二聚化，并提出这反映了底物结合结构域的闭合构象。我们的研究结果提供了新的见解SGTA的结构复杂性，并提供了一个新的基础，底物结合和释放的C-末端区域的机制研究。本文的在线版本（10.1186/s12915-018-0542-3）包含补充材料，可供授权用户使用。
Protein quality control mechanisms are essential for cell health and involve delivery of proteins to specific cellular compartments for recycling or degradation. In particular, stray hydrophobic proteins are captured in the aqueous cytosol by a co-chaperone, the small glutamine-rich, tetratricopeptide repeat-containing protein alpha (SGTA), which facilitates the correct targeting of tail-anchored membrane proteins, as well as the sorting of membrane and secretory proteins that mislocalize to the cytosol and endoplasmic reticulum-associated degradation. Full-length SGTA has an unusual elongated dimeric structure that has, until now, evaded detailed structural analysis. The C-terminal region of SGTA plays a key role in binding a broad range of hydrophobic substrates, yet in contrast to the well-characterized N-terminal and TPR domains, there is a lack of structural information on the C-terminal domain. In this study, we present new insights into the conformation and organization of distinct domains of SGTA and show that the C-terminal domain possesses a conserved region essential for substrate processing in vivo. We show that the C-terminal domain region is characterized by α-helical propensity and an intrinsic ability to dimerize independently of the N-terminal domain. Based on the properties of different regions of SGTA that are revealed using cell biology, NMR, SAXS, Native MS, and EPR, we observe that its C-terminal domain can dimerize in the full-length protein and propose that this reflects a closed conformation of the substrate-binding domain. Our results provide novel insights into the structural complexity of SGTA and provide a new basis for mechanistic studies of substrate binding and release at the C-terminal region. The online version of this article (10.1186/s12915-018-0542-3) contains supplementary material, which is available to authorized users.
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影响因子：
3.7
作者：
Darby JF;Krysztofinska EM;Simpson PJ;Simon AC;Leznicki P;Sriskandarajah N;Bishop DS;Hale LR;Alfano C;Conte MR;Martínez-Lumbreras S;Thapaliya A;High S;Isaacson RL
通讯作者：
Isaacson RL
影响因子：
4.8
作者：
Paul, Atanu;Garcia, Yenni A.;Cox, Marc B.
通讯作者：
Cox, Marc B.
影响因子：
4.6
作者：
Krysztofinska EM;Martínez-Lumbreras S;Thapaliya A;Evans NJ;High S;Isaacson RL
通讯作者：
Isaacson RL
SGTA与RPN13的结合选择性调节蛋白质质量控制。
影响因子：
4
作者：
Leznicki P;Korac-Prlic J;Kliza K;Husnjak K;Nyathi Y;Dikic I;High S
通讯作者：
High S
影响因子：
6.1
作者：
Petoukhov MV;Franke D;Shkumatov AV;Tria G;Kikhney AG;Gajda M;Gorba C;Mertens HD;Konarev PV;Svergun DI
通讯作者：
Svergun DI